1. Field of the Invention
This invention relates to a general process for alpha-arylation of carbonyl-containing compounds, and more particularly to a general process for synthesizing alpha-arylated carbonyl-containing compounds from arylating compounds and carbonyl containing compounds using a transition metal catalyst.
2. Description of the Related Art
The palladium-catalyzed coupling to form C--C bonds between aryl and vinyl halides or triflates and a carbon nucleophile is one of the most widely used transition metal-catalyzed reactions. (Stille, J. K. Angew. Chem., Int. Ed. Engl., 25:508-524 (1986); Miyaura, N. et al., Chem. Rev., 95:2457-2483 (1995); Negishi, E. Acc. Chem. Res., 15:340-348 (1982)). The related cross-coupling reactions involving ketone enolates as the nucleophile are also very important commercially. However, this class of cross-coupling reactions has been limited to tin enolates, silyl-enol ethers in combination with tin fluoride, intramolecular examples, or examples with acid ketones and metal ion catalysts in low yields (Kosugi, M. et al., Bull. Chem. Soc. Jpn., 57:242-246 (1984)).
Many transition metal-catalyzed approaches to ketone arylation using pre-formed main group enol ethers (Carfagna, C. et al., J. Org. Chem., 56:261-263 (1991); Durandetti, M. et al., J. Org. Chem. 61:1748-1755 (1996); Fauvargue, J. F. et al., J. Organomet. Chem., 177:273-281 (1979)) or bismuth or lead reagents (Barton, D. H. R. et al., Tet. Letters, 27:3619-3522 (1986); Barton, D. H. R. et al., J. Chem. Soc., Perkin Trans. 1:1365-1375 (1992)) have been investigated. However, use of toxic main-group reagents, low product yields, and multi-step preparation of compounds make these procedures particularly difficult to exploit commercially. In addition, arylation using a metal halide in the absence of a chelating ligand has been shown (Satoh et al., Angew. Chem. Int. Ed. Engl. 36:1740-1741 (1997)); however, the yield of product is unacceptably low for commercial purposes.
It would be advantageous to prepare alpha-aryl carbonyl-containing compounds from arylating compounds such as aryl halides and/or aryl sulfonates because aryl halides are generally inexpensive and readily available, while aryl sulfonates are easily prepared from phenols. However, to date, the simple direct reaction of an arylating compound and a carbonyl-containing compound (such as a ketone) with base in the presence of a transition metal catalyst has not been reported.
In view of the above, a need exists for a general and efficient process of synthesizing alpha-aryl carbonyl-containing compounds. The discovery and implementation of such a process would simplify the preparation of commercially significant organic alpha-aryl carbonyl-containing compounds and would enhance the development of novel pharmacologically active compounds. The present invention is believed to be an answer to that need.